The unit has focussed on signal transduction abnormalities in Bipolar Affective Disorder and Alzheimer's disease. Highlights of the past year include: 1. Leukocytes from untreated manic patients reveal small increases in the levels of Gsalpha (45kDa) compared to controls or lithium treated bipolars. Long term lithium treatment of bipolars is associated with a significant increase in the pertussis toxin catalyzed (32P) ADP- ribosylation of Gi, and a decrease in the levels of Galphag. 2. In the past year platelet and leukocyte subcellular fractions have been collected from 50 bipolar I patients. The levels and functional state of various components of signal transduction (including G protein subunits and PKC isozymes) is currently being investigated in these tissues. 3. Platelets from patients with Alzheimer's disease show decreases in the levels of selected PKC isozymes, which are more pronounced following 3 weeks of lithium administration. 4. Abnormalities in alpha2/Gi signal transduction pathway in bipolar illness is being investigated by multiple biochemical measures in response to intravenous idazoxan administration. Altered norepinephrine responses to idazoxan are correlated with measures characterizing alpha2 inhibition of platelet A.C. activity.